Consistent findings from both animal models and human studies of drug addiction support the roles of stress as a precipitant of relapse and as a vulnerability factor. The conceptual framework of this revised proposed research plan remains based on the contention that drug addiction is a stress-related disorder with definable neural events that link early life and acute stress to both the development of drug addiction and its chronically relapsing nature. The neural correlates of the effects of acute (i.e., stress experience mental imagery) and early (i.e., childhood abuse) stressors on motivation for relapse to drug seeking behavior and on frontal cortical functions that represent opponent processes to addiction would be defined using functional magnetic resonance imaging (fMRI) in cocaine-dependent men and women. Aim 1 of the project would use z-SAGA fMRI to define those neural activations that link an acute stressor (stress mental imagery) to an enhanced motivation for drug use in cocaine-dependent men and women without early trauma histories, and compare the functional anatomy of stress-induced and conditioned drug cue (drug use imagery)-induced cocaine craving in a within-subjects design. A hypothesis that acute stressors and conditioned cocaine cues activate distinct drug craving-related neural substrates in addicted individuals would be tested. Aim 2 would compare cocaine- dependent women and men with childhood abuse histories to those without (Aim 1) to define the effect of early life stress on the neural correlates of stress-induced, and drug cue-induced, cocaine craving. A hypothesis that childhood abuse is associated with exaggerated drug incentive and related neural responses to acute stress, as well as conditioned drug cues, in cocaine-dependent individuals would be tested. Aim 3 would compare groups of non-drug- dependent men and women with and without early life trauma histories on measures of impulse regulation (stop task), and reward valuation and decision making (reward task). A hypothesis that the increased risk for drug abuse and addiction associated with childhood abuse is related to deficits in the prefrontal cortical regulation of cognitive behaviors central to the addiction process would be tested. Sex differences in the roles of stress in cocaine addiction would be assessed with the expectation that women exhibit exaggerated roles compared to men. By integrating the Substance Abuse Treatment Program at the Atlanta VAMC with the childhood abuse research team of the Emory Conte Center for the Neurobiology of Mental Disorders, we propose to identify the neural processing mechanisms that couple acute and early life stress to an increased acquisition and maintenance of drug abuse and addiction. [unreadable] [unreadable] [unreadable]